1. Field of the Invention
This invention relates to the field of biochemistry, and provides pharmaceutical agents which are antiestrogens and antiandrogens.
Estrogen is transported throughout the body in the bloodstream and passively enters cells. However, only certain tissues exhibit responses to the hormone and are accordingly designated target tissues. These target tissues are characterized by specific estrogen receptors. The interaction of estradiol with estrogen receptors is an early event in a complex series of events which result in an estrogenic response. The uterus is considered the primary target tissue for estrogen. It is rich in estrogen receptors and exhibits dramatic growth under the influence of estradiol. Consequently the uterotropic response of rodents provides a reproducible model for the evaluation of estrogenic and antiestrogenic activity as well as the study of interactions with estrogen receptors.
A relationship has been established between estrogen sensitivity or dependency and the occurrence of estrogen receptors in certain mammary cancers as well as in benign fibrocystic disease of the breast. The neutralization of estrogen influence on those tissues is expected to benefit patients with those conditions by causing regression or preventing recurrence of the condition.
Antiestrogens antagonize the action of estrogens in animal models and display clinical efficacy in most mammary cancers which contain estrogen receptors. They interact with estrogen receptors, and elicit partial estrogenic response. Thus, the ability to antagonize the effect of estradiol is related to and restricted by the degree of intrinsic estrogenicity of the compound. The compound that evokes the greatest degree of estrogen antagonism, accordingly, is expected to be the most beneficial.
Similarly, androgen circulates and is taken up by androgen-receptive tissues. Prostatic cancer is a clinical condition believed to have androgen dependency or sensitivity, as does the condition known as benign prostatic hypertrophy. Accordingly, anti-androgens are in demand, and anti-androgenic testing is successfully carried out based on the rapid growth of the rodent prostate under the influence of androgen.
2. State of the Art
Antiestrogens have been under investigation for some years, and at least one such compound is presently being sold for palliative cancer therapy. This drug is tamoxifen, 1-(4-.beta.-dimethylaminoethoxyphenyl)-1,2-diphenylbut-1-ene.
Another group of known antiestrogens are the dihydronaphthalenes of U.S. Pat. No. 4,230,862, of Suarez and Jones. The most important compound of this group is trioxifene mesylate, 2-[4-(2-pyrrolidinoethoxy)-benzoyl]-1-(4-methoxyphenyl)-3,4-dihydronaphtha lene, methanesulfonic acid salt. Trioxifene has been clinically tested in cases of advanced breast cancer.
Another group of antiestrogens are the benzothiophenes of Jones and Suarez, U.S. Pat. No. 4,133,814. Tests of one of their compounds, 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-pyrrolidinoethoxy)benzoyl]benzo[b]th iophene, have been published by Black and Goode, Life Sciences 26, 1453-58 (1980). The same article also discussed similar tests of tamoxifen and trioxifene as estrogens and antiestrogens. The authors concluded that the above benzothiophene was considerably more effective as an antiestrogen, and considerably less estrogenic, than either tamoxifen or trioxifene.